Chalcone derivatives and preparation thereof

ABSTRACT

W-AMINOALKOXYCHALCONES OF THE FOLLOWING GENERAL FORMULA:   1-(((R&#39;&#39;-N(-R&#34;)-(CH2)N-O-)-PHENYL)-CH=CH-CO-),2-R1,3-R2,   4-R3,5-R4,6-R5-BENZENE   AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS HAVING SUPERIOR ANTIHYPERTENSIVE ACTIVITY AND THEREFORE USEFUL FOR PREVENTING AND TREATING HYPERTENSION IN HUMAN, COMPOSITION SUITABLE FOR SUCH PREVENTION AND TREATMENT AND METHODS FOR THE PREPARATION OF THE SAID W-AMINOALKOXYCHALCONES.

Patented Aug. 6, 1974 US. Cl. 260-24011 15 Claims ABSTRACT OF THE DISCLOSURE w-Aminoalkoxychalcones of the following general formula:

R: R: l I -on=on-c o-Q-m and their pharmaceutically acceptable acid addition salts having superior antihypertensive activity and therefore useful for preventing and treating hypertension in human, composition suitable for such prevention and treatment and methods for the preparation of the said w-aminoalkoxychalcones.

The present invention relates to chalcone derivatives, more particularly relates to w-aminoalkoxychalcones and their pharmaceutically acceptable acid addition salts and methods for the preparation thereof and composition containing the chalcone derivatives.

Hitherto, there has been known that some chalcone derivatives, i.e.

2- (Z-dimethylaminoethoxy) -3 ',4,5'-trimethoxychalcone,

2- Z-dimethylaminoethoxy) -3 ',4'-dimethoxychalcone,

2- (Z-dimethylaminoethoxy) -2,4-dimethoxychalcone,

2- (3 -dimethylarninoprop oxy) -3 ',4' ,5 -trimetl1oxychalcone,

and

4- (Z-dimethylaminoethoxy) -3 ',4,5 -trimethoxychalcone can be prepared by reacting a dimethylaminoalkoxybenzaldehyde and a substituted acetophenone or by reacting a hydroxychalcone with a dimethylaminoalkyl chloride and that the chalcone derivatives have antihypertensive properties (US. Pat. No. 3,407,233). Furthermore, it has been reported that some chalcone derivatives, i.e.

2- (Z-dimethylaminoethoxy chalcone citrate,

4- (Z-dimethylaminoethoxy) chalcone hydrochloride, 2- (2-diethylaminoethoxy chalcone citrate,

4- (3 -diethylaminoprop oxy chalcone hydro chloride, 4- Z-dimethylaminoethoxy) chalcone citrate,

4- (3-dimethylaminopropoxy) chalcone hydrochloride, 4- Z-dimethylaminoethoxy chalcone hydrochloride, 4-( Z-diethylaminoethoxy chalcone citrate,

4-( 2-diisopropylaminoethoxy chalcone, and

4- (2-diethylaminoethoxy) chalcone citrate were evaluated with regard to their hypotensive potency and ability to inhibit the pressor response to epinephrine and occlusion of the carotid arteries in anesthetized normotensive dogs and they exhibited relatively low specificity, low potency and transient duration of action (Journal of the American Pharmaceutical Association, vol. 47, No. 9, pp. 640-645, 1958).

It has been studied to find out other chalcone derivatives having superior pharmacological activities. Then,

there have now been found novel chalcone derivatives, more particularly novel w-aminoalkoxychalcones having superior pharmacological activities and further new methods of the preparation thereof.

An object of the present invention is to provide novel w-aminoalkoxychalcones and their pharmaceutically acceptable acid addition salts having superior pharmacological activities.

Another object of the present invention is to provide methods for preparing, the said novel w-aminoalkoxychalcones and their pharmaceutically acceptable acid addition salts.

Another object of the present invention is to provide pharmaceutical compositions containing the said novel chalcone derivatives.

A further object of the present invention is to provide method for preventing and treating hypertension in human by administering the said chalcone derivatives to patients.

These and other objects will more clearly appear hereinafter.

The novel chalcone derivatives of the present invention can be illustrated by the following general formula:

wherein R R R R and R are, the same or different, hydrogen atom, hydroxyl group, nitro group, an alkyl group having 1 to 3 carbon atoms, a halogen atom selected from chlorine, bromine and iodine and an alkoxy group having 1 to 3 carbon atoms, R and R" are, the same or different, each hydrogen atom, an alkyl group having 1 to 4 carbon atoms, allyl group or may be bound together with nitrogen atom to form a fiveor six-membered heterocyclic group in which there may contain other hetero atom, such as nitrogen, oxygen and sulfur, provided that R and R" are, the same or different, each an alkyl group having 2 to 4 carbon atoms, allyl group or may be bound together with nitrogen atom to form a fiveor six-membered heterocyclic group in which there may contain other hetero atom, such as nitrogen, oxygen and sulfur, when at least two of R R R R and R are methoxy group, or the group o (CH7)nN may be substituted at ortho, metha or para position, preferably at ortho position.

Suitable examples of the heterocyclic group defined above for group may be pyrrolidino, oxazolidino, piperidino, morpholino, thiatnorpholino and piperazino group which may have one or more substituents selected from an alkyl group having 1 to 3 carbon atoms, a hydroxyalky group having 1 to 3 carbon atoms, phenyl group whichmay be further substituted by hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or a halogen atom selected from chlorine, bromine and iodine, benzyl group which may be further substituted by hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or a halogen atom selected from chlorine, bromine and iodine, formyl group and the like.

Suitable compounds are one in which R and R are hydrogen atom and R R and R are methoxy group or R R R and R are hydrogen atom and R is a member selected from methoxy group and a halogen atom.

Suitable examples of the present w-aminoalkoxychalcones are 2- (2-piperidinoethoxy -4'-rnethoxychalcone,

2- (Z-piperidinoethoxy) -3 ',4',5'-trimethoxychalcone,

2- (3-piperidinopropoxy) -4-chlorochalcone,

2- 3- (N'-methylpiperazino propoxy] -4-chlorochalcone,

2- 3-( N'-methylpiperazino propoxy] -4-rnethoxyehalcone,

2- 2-(N'-methylpiperazino ethoxy] -4'-methoxychalcone,

2- (2- diethylaminoethoxy) -4'-methoxychalcone,

2- S-diethylaminopropoxy -3 -,4',5-trimethoxychalcone,

2- [2- N-phenylpiperazino) ethoxy] -4'-methoxychalcone,

2- (Z-morpholinoethoxy) -4-chlorochalcone,

2- (2-dimethylaminoethoxy) -4'-chloro chalcone,

2- Z-dimethylaminoethoxy) -4-methoxychalcone,

2-( Z-diethylaminorne thoxy) -4'-'chlorochalcone,

2- (3 -diethyaminopropoxy -4'-methoxychalcone,

3-(2-dimethyaminoethoxy -4'-methoxychalcone,

2- 3-morpholinopropoxy -3 ',4,5'-trimethoxychalcone,

2- [2- (N'-methylpiperazino ethoxy] -4'-chlorochalcone,

2- Z-dimethylaminoethoxy -4'-hydroxychalcone,

2-{3- [N'- (Z-hydroxyethyl piperazino] propoxy}-4'- methoxychalcone,

2- 2-piperidinoethoxy) -4-bromochalcone,

4- 3-( N-methylpiperazino) propoxy] -4'-chlorochalcone,

2-(2-morpholinoethoxy -3 ,4,5 '-trimethoxychalcone,

2-( 3-piperidinopropoxy )-3',4,5'-trimethoxychalcone,

2- B-diethylaminopropoxy) -4'-chlorochalcone,

2- 2-diethylamino ethoxy) -4-methylchalcone, and

2- (Z-dimethylaminoethoxy) -2'-hydroxychalcone.

One method for the preparation of the present compounds (Method A) can be illustrated as follows:

n a an (III) 1 I -on=on-o -R3 (I) 0 (CH2) 11X (II) R R4 wherein X is a halogen atom selected from chlorine, bromine and iodine, tosyloxy group (i.e. p-toluenesulfonyloxy group) and hydroxyl group, and R R R R R R, R" and n are the same as defined above.

In Method A, an w-substituted alkoxychalcone (II) is reacted with an amine (III) to give desired w-aminoalkoxychalcone (I). The reaction can be carried out at room temperature or preferably at a reflux temperature in a suitable organic solvent, such as benzene, toluene and xylene or without solvent. The reaction period is a few to ten several hours, preferably 3 to hours.

The starting w-substituted alkoxychalcone (II) can be prepared by the following methods.

. wherein X is a halogen atom and tosyloxy group and R R R R R R, R", n and X are the same as defined above.

In the former method, a hydroxychalcone (IV) is re acted with an w-substituted alkyl reagent (V), e.g. wchloroalkyl bromide in the presence of alkali in a suitable organic solvent, such as a lower alcohol, e.g. methanol, ethanol and propanol to give w-substituted al-koxychalcones (II). The reaction can be carried out by heating at a reflux temperature of the solvent for a few to ten several hours, preferably 3 to 10 hours. The alkali used in the above reaction may be an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide or an alkali metal alkoxide, such as sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide. In the above reaction, an alkali metal salt of the hydroxychalcone can be also used instead of that the free hydroxychalcone is reacted in the presence of alkali.

In the latter method, an iii-substituted alkoxybenzaldehyde (VI) is condensed with an acetophenone (VII) in the presence of a base or an acid to give an w-substituted alkoxychalcone (II). The condensation reaction can. be smoothly carried out at room temperature or preferably under wateror ice-cooling in an inorganic or organic solvent, such as water, methanol, ethanol, ethyl acetate, dioxane and a mixture thereof. The reaction period may be varied according to the reaction substance, but usually several ten minutes to several hours, more particularly 1 to 5 hours. The base used in the reaction may preferably be an inorganic base, such as an alkali metal hydroxide, e.g. sodium hydroxide and potassium hydroxide and an alkali metal alkoxide, e.g. sodium methoxide, so dium ethoxide, potassium methoxide and potassium ethoxide, an organic base, such as trimethylamine and triethylamine and the like, and the acid may be an inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid and the like.

According to the present condensation reaction, the w-substituted alkoxychalcones (II) can be obtained in high yield and readily precipitated and then isolated from the solvent in a form of high purity. Thus obtained compounds (II) can be therefore used in next step without further purification.

When X group of thus obtained compounds (II) is hydroxyl group, they may be further subjected to halogenation or tosylation to give the compounds, in which X is a halogen atom or tosyloxy group, by conventional methods, e.g. by reaction with a halogenating agent, such as thionyl chloride or tosyl chloride.

The starting (vi-substituted alkoxybenzaldehyde (VI) of the latter method can be readily prepared by reacting a hydroxybenzaldehyde with corresponding w-substituted alkyl reagent (V), e.g. w-chloroalkyl bromide at a reflux temperature for several to ten several hours in a suitable solvent, such as methanol, ethanol, benzene and toluene in the presence of alkali, such as sodium, potassium, sodium hydroxide, potassium hydroxide, sodium hydride and sodium amide.

Another method for the preparation of the present compounds (Method B) can be illustrated as follows:

wherein R R R R R R R", n and X are the same as defined above.

According to this method B, a benzoylcoumarin (VHI) is reacted with an w-aminoalkyl halide (IX) in the presence of alkali in a suitable organic solvent to give the desired compound (I'). The reaction can be carried out by heating at a reflux temperature of the organic solvent for a few to ten several hours, preferably 3 to hours.

The alkali used in the above reaction may preferably be an alkali metal alkoxide, such as sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide and an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide and the like, and the organic solvent may be benzene, toluene, Xylene, dioxane, tetrahydrofuran, dimethylformamide and the like.

The starting benzoylcournarin (VIII) can be prepared by reacting a lower alkyl ester of the corresponding benzoylacetic acid and salicylaldehyde in the presence of a secondary amine in an organic polar solvent. The reaction can be carried out by heating at a reflux temperature of the solvent for several ten minutes to several hours. The secondary amine may be dimethylamine, dipropylamine, dibutylamine, pyrrolidine, piperidine and the like, and the polar solvent may be alcohols, such as methanol, ethanol, propanol and butanol, pyridine, 1,2-dimethoxyethane and the like.

Alternatively, the present compounds can be prepared by the following methods (Methods C and D) which have been known in the above described US. Pat. No. 3,407,- 233. These methods are illustrated as follows, respectively.

wherein R R R R R R, R", n and X' are the same as defined above.

In the former method (Method 'C), a hydroxychalcone (X) is reacted with an w-aminoalkyl halide (IX) in the presence of alkali in a suitable organic solvent to give the desired compound (I).

The reaction can be carried out by heating at a reflux temperature of the solvent for a few to several hours. The alkali used in the above reaction may be an alkali metal hydroxide, such as sodium hydroxide and potassium hydroxide, sodium hydride, sodium amide, sodium and the like, and the organic solvent may be ethanol, benzene, toluene, xylene and the like.

In the latter method (Method D), an w-aminoalkoxybenzaldehyde (XI) is condensed with an acetophenone (VII) in the presence of a base or an acid in the same manner as described in Method A, the latter method for the preparation of the starting w-substituted alkoxychalcone (II).

In Methods C and D, it is essential to use w-aminoalkyl compounds. Therefore, they are not necessarily preferable when the w-aminoalkyl compounds are unavailable, for example for the preparation of w-heterocyclic group substituted alkoxy derivatives: the group in the formula (I) being a heterocyclic group. On the contrary, in the novel Method A, any w-aminoalkyl compound is not used but amines themselves can be used, and therefore, various kinds of amine derivatives can be 6 readily prepared. In Method A, there is further advantage that the w-substituted alkoxychalcones (11) obtained by the condensation reaction can be easily isolated from the reaction mixture in good yield and in high purity, as described hereinbefore.

Furthermore, for the preparation of 3',4',5-trimethoxychalcones, Method D is not preferable since the starting 3,4,5-trimethoxyacetophenone: R R and R being methoxy group and R and R being hydrogen atom in formula (VII) is unavailable and it is prepared from 3,4,S-trimethoxybenzoic acid in low yield. On the other hand, in the novel Method B, 3,4,5-trimethoxyacetophenone is not used and the starting (3,4,5-trimethoxybenzoyl)coumarin can conveniently be prepared from available 3,4,5-trimethoxybenzoic acid in good yield. Therefore, the Method B is advantageous especially for the preparation of 3',4',5'-trirnethoxychalcones.

When the w-aminoalkoxychalcones (I) prepared by the above methods are a free base, they can be readily converted into their acid addition salts by a conventional method, e.g. treatment of the former with an acid in a suitable solvent, such as water, methanol, ethanol, chloroform and ether. The acid may be an inorganic acid, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid and phosphoric acid and an organic acid, such as maleic acid, succinic acid, oxalic acid, citric acid, malic acid, tannic acid and gallic acid.

According to the present invention, the known chalcone derivatives, i.e. 2(or 4)-dimethylaminoalkoxy di( or more) methoxychalcone and 2(or 4)-dialkylaminoalkoxychalcone which may be illustrated by the following formula:

present novel Methods A and B. Therefore, the present invention provides also the novel methods for the preparation of the known chalcone derivatives.

The w-aminoalkoxychalcones I) and their pharmaceutically acceptable acid addition salts of the present invention possess superior pharmacological activities, e.g. antihypertensive, vasodilative activities, and are therefore useful as medicaments, especially for prevention and treatment of hypertension.

The w-aminoalkoxychalcones ('I) and their pharmaceutically acceptable acid addition salts can be administered orally by conventional methods with conventional pharmaceutical carriers in human.

They can be used in a form of tablets, capsules, powders or in a liquid form, such as solutions, emulsions, suspensions or syrups.

In the preparation of tablets containing the present compounds there may be employed various non-toxic pharmaceutical carriers which are compatible with the present compounds, such as excipients, e.g. microcrystah line cellulose, lactose, starch or the like, lubricants, e.g. silicic acid anhydride, magnesium stearate, talc, sodium laurylsulfate or the like and binder, e.g. starch paste, lactose, mannitol, magnesium trisilicate, gelatin or the like, as is well known in the art.

When they are administered in a liquid form, there can be used conventional liquid carrier such as water.

For prevention and treatment of hypertension in human the required dosage per day of the present compounds is within the range of 0.01 to mg. per kg. of body weight when administered orally. A preferred dosage per day is within the range of 0.1 to 30 mg. per kg. of body weight, more particularly the range of 1 to 10 mg. per kg. of body weight. Consequently, the present pharmaceutical composition for preventing and treating hypertension in adults contains the present compounds in the range of about 100 to 300 mg. per daily dosage unit.

The total dosage may be administered in smaller portions three or four times daily as determined by the attending physician.

The preparation of the present w-aminoalkoxychalcones and their pharmaceutically acceptable acid addition salts are set out in the following examples which are illustrative but not limiting.

EXAMPLE 1 (a) To a solution of 13.0 g. of 2hydroxy-4'-chlorochalocone in 30 ml. of methanol was added dropwise a solution of 2.2 g. of sodium hydroxide in 70 ml. of methanol. After the mixture was refluxed for 10 minutes, 28 g. of l-chloro-Z-bromoethane was added and the mixture was further refluxed for 5 hours. After filtering the reaction mixture, the filtrate was distilled to remove methanol and the unreacted 1-chloro-2-bromoethane and then extracted with ether. The ether extract was washed with dilute hydrochloric acid and water, dried over anhydrous sodium sulfate and distilled to remove ether. Thus obtained residue was recrystallized from ethanol to give 14.2 g. of 2-(2-chloroethoxy)-4'-chlorochalcone having a melting point of 114-116 C.

(b) To a solution of 3.2 g. of 2-(2-chloroethoxy)-4'- chlorochalcone obtained above in 20 ml. of toluene was added 2.2 g. of N-methylpiperazine. The mixture was refluxed for 6 hours. After cooling, the reaction mixture was filtered. The filtrate was repeatedly extracted several times with dilute hydrochloric acid. Thus obtained acidic solution was made alkaline with sodium carbonate and then extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and treated with a saturated solution of hydrogen chloride in ether. The resulting precipitate was filtered. The residue was recrystallized from ethanol to give 29 g. 'of 2-[2-(N'- chalcone in 50 ml. of methanol was gradually added dropwise a solution of 0.8 g. of sodium hydroxide in 20 ml. "of methanol. After the mixture was refluxed for 10 minutes, 11.5 g. of l-chloro-2-bromoethane was further added dropwise and then the mixture was refluxed for 5 hours. The reaction mixture was distilled off under reduced pressure to remove methanol and unreacted l-chloro-Z- bromoethane. The residue was extracted with ether. The extract was washed with dilute hydrochloric acid, 5% aqueous sodium carbonate and water in order, dried and distilled to remove ether. The resulting residue was recrystallized from ethanol to give 4.8 g. of 2-(2-chloroethoxy)-4-methoxychalcone having a melting point of 109-110 C.

(b) To a solution of 3.2 g. of 2-(2-chloroethoxy)- 4'-methoxychalcone obtained above in 30 ml. of toluene was added 3.6 g. of N-phenylpiperazine and the mixture was refluxed for 5 hours. After cooling, the reaction mixture was filtered. The filtrate was repeatedly extracted several times with dilute hydrochloric acid. Thus obtained acidic solution was made alkaline with sodium carbonate and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and then treated with a saturated solution of hydrogen chloride in ether. The resulting precipitate was filtered and then dissolved into chloroform. The chloroform solution was washed with water, dried over anhydrous sodium sulfate and then distilled 01f to remove chloroform. The residue was recrystallized from ethanol to give 2.8 g. of ".-[2 (N'- phenylpiperazino)ethoxy] 4' methoxychaicone hydrochloride (Compound No. 2) having a melting point of 192-195 C.

Elementary analysis for C H N O -2HCl.Calculated: C, 70.06%; H, 6.51%; N, 5.84%; Cl, 7.40%. Found: C, 70.19%; H, 6.68%; N, 6.06%; Cl, 7.71%.

EXAMPLES 3-28 In the same manner as described in Examples 1 and 2, there were prepared various w-disubstituted aminoalkoxychalcones having the following formula:

methylpiperazino)ethoxy]-4' chlorochalcone dihydro- R1 chloride (Compound No. 1) having a melting point of I 21' 223 Q GH=CH-COR3 salt Elementary analysis for C H N O 'Cl-2HCl.-Calcu R, lated: c, 57.72%; H, 5.94%; N, 6.12%; 01, 23.23%. R4 Found: C, 57.37%; H, 6.07%; N, 6:50%; Cl, 23.07%. a n

RI! EXAMPLE 2 (a) To a solution of 5.1 g. of 2-hydroxy-4'-methoxy- They are shown in Table I.

TABLE I Groups N Melting Elementary analysis E x. H point Comp. tvo. R R9 R3 R4 n Salt C.) C H N Cl Br No 3 H 0011 H 3 HUI-H2O 98-100 0* 67.97 7.37 3.23 8.36 3

4.. /fi II 0011 H. 3 21:10] 223-225 0 60.48 6.70 5.64 14.28 4

-N NCHzOHzOI-I F 60.33 7.07 5.49 1235 H 0011 H 3 21101-1] 210-211 C 60.50 6.08 5.88 14.88 5 v -N /NCH; 21120 F 60. 7. 53 5. 74 15.01

6- Sameasabove H 01 8 21101 11 225-229 C 57.81 6.26 5.86 22.26 6

01 3 21701 220-223 C 62.45 5.04 4.86 18.44 '7 -N m-om-Q-oona F 62.45 6.23 4. 61 18.36

8 -OH 00H, 0011 0011 3 H01 -173 0 63.35 6.96 3.21 8.13 s F 63.22 7.13 3.16 8.35

9.-...- Sameasabove OCH; OOHa OCH; 2 HC] 167-169 C 62.63 6.69 3.32 8.40 9

Comp. Bl N Elementary analysis Melting point; C.)

at Salt TABLE I-Continued OCHs H Groups Ex. No.

5302 3 6785 8 &&Qwom7 7 11 88 720 613M709 06 82 11 75 6 6 6 6 56 608130 113611 mwmfimm CFCFCF OCH; 2 H01 OCH;

2 CIIOOH 154-155 COOH 3 Same 119-121 OCH;

OCH;

C1 2 HCl 0 CH OCH 2 HO].

Cl 3 HCl 0 CH OCH; 3 HCl-l/ ZHzO OCHa OCH;

(b) 3.0 g. of 2-(3-chloropropoxy)-4'-bromochalcone obtained above and 2 g. of N-methylpiperazine were dissolved in 30 ml. of anhydrous toluene. The mixture was refluxed for 7 hours.'To the reaction mixture was added dium hydroxide. Toluene layer was separated from the mixture and extracted with dilute hydrochloric acid. The extract was made alkaline with sodium hydroxide and extracted with ether. The ether extract was washed with real hydrochloric acid was added to the ether extract. The resulting precipitate was separated by filtration and recrystallized from ethanol to give 2.1 g. of 2-[3-(N'-methylpiperazino)propoxy]-4-bromochalcone dihydrochloride C. as faint yellow scales.

Elementary analysis for C H N O Br 2HC1 /2H O.- Calculated: C, 52.59%; H, 5.56%, N, 5.33%;Cl, 13.50%; Br, 15.21%. Found: C, 52.63%; H, 5.48%; N, 5.42%; Cl,

EXAMPLE 30 (a) To a solution of 4 g. of 2-(3-chloropropoxy)-benzaldehyde and 3.1 g. of 4-chloroacetophenone in 25 ml. 75 of ethanol was added dropwise with agitation a solution OCH C=Calcu1ated; F=Found.

EXAMPLE 29 (a) To a solution of 4 g. of 2-(3-chloropropoxy)-benzaldehyde and 4 g. of 4-bromoacetophenone in 25 ml. of ethanol was added dropwise with agitation a solution or w t nd th the mixture wa made alkaline with so- 1 g. of sodium hydroxide in 2.5 m1. of water under icecooling. The precipitated crystals were separated by filtration, washed With water and then recrystall z d f ethanol to give 7- of p p y)- water and dried over anhydrous sodium sulfate and ethe- Elementary analysis for C H O ClBr.-Calculated: C, 56.94%; H, 4.25%; Cl, 9.34%; Br 21.05%. Found: C,

4.05%; Cl, 9.27%; Br, 20.89%. The starting 2-(3-chloropropoxy)benzaldehyde was pre- (Compound No. 29) having a melting point of 209213 pared as follows:

To 300 m1. of ethanol was dissolved 4.6 g. of sodium and then were added with agitation 24.4 g. of salicylaldehyde, 0.1 g. of sodium iodide and 64 g. of 3-chloropropyl cooling. The mixture was further agitated for 3 hours under ice- 4-bromochalcone having a melting point of 75-77 C.

bromide. The mixture was refluxed for 8 hours and fil- 13.44%; Br 15.16%. tered off to remove the dissolved substance. The filtrate was concentrated to give an oily substance. The resulting oily substance was distilled in vacuo to give 31 g. of the desired product having a boiling point of 148 C. at 4 mm. Hg.

of 1 g. of sodium hydroxide in 2.5 ml. of water under icecooling. The mixture was further agitated for 3 hours under ice-cooling. The precipitated crystals were separated.

by filtration, washed with water and then recrystallized from ethanol to give 6.4 g. of 2-(3-chloropropoxy)-4- chlorochalcone having a melting point of 78-79 C.

Elementary analysis for C H O Cl .Calculated: C, 64.49%; H, 481%; C1, 21.15%. Found: C, 64.33%; H, 4.92%; Cl, 20.87%.

Alternatively, the 2-(3-chloropropoxy)-4'-chlorochal cone was prepared by the following methods.

(1) To a solution of 300 mg. of sodium dissolved into ml. of ethanol was added dropwise with agitation a solution of 1.99 g. of 2-(3-chloropropoxy)benzaldehyde and 1.55 g. of 4-chloroacetophenone in ml. of ethanol under ice-cooling. The mixture, in which crystals were precipitated after a few minutes, was reacted with agitation for 3 hours under ice-cooling. To the reaction mixture was added water and the crystals were separated by filtration and dried to give 3.3 g. of the desired compound.

(2) To a solution of 1.99 g. of 2-(3-chloropropoxy)- benzaldehyde and 1.55 g. of 4-chloroacetophenone in ml. of ethanol was added with agitation 1 m1. of concentrated sulfuric acid. The mixture was added onto ice water and extracted with benzene. The benzene layer was washed with water, dried and evaporated to remove benzene. To the oily residue was added n-hexane and the resulting crystals were filtered to give 2.6 g. of the desired compound.

(3) To a solution of 1.99 g. of 2-(3-chloropropoxy)- benzaldehyde and 1.55 g. of 4-chloroacetophenone in 50 ml. of ethyl acetate was saturated dried hydrogen chloride gas. The flask including the mixture was stopped and allowed to stand for 4 days. The reaction mixture was evaporated at about 50 C. under reduced pressure to remove ethyl acetate. The oily residue was heated on boiling water-bath under reduced pressure for 1 hour. The resulting crystals were washed with n-hexane and filtered to give 1.7 g. of the desired compound.

(1)) 5 g. of 2-(3-chloropropoxy)-4-chlorochalcone and 5.25 g. of N-benzylpiperazine were dissolved into 30 ml. of toluene. The mixture was refluxed for 8 hours. The precipitating N-benzylpiperazine was filtered ofi? and the filtrate was washed with Water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. To the oily residue was added alcoholish hydrochloric acid. The resulting crystals were recrystallized from methanol to give 7.1 g. of 2-[3-(N'-benzylpiperazino) propoxy] 4' chlorochalcone dihydrochloride (Compound No. 30) having a melting point of 225228 C. (decomposition).

Elementary analysis for C H N O Cl-2HCl.Calculated: C, 63.56%; H, 6.07%; N, 5.11%; Cl, 19.41. Found: C, 63.33%; H, 6.02%; N, 5.31%; Cl, 18.91%.

EXAMPLE 31 A solution of 5 g. of 2-(3-chloropropoxy)-4'#chlorochalcone prepared in the same manner as described in Example 30(a) and 5.75 g. of N-(Z-methoxyphenyl) piperazine in 30 ml. of toluene was refluxed for 8 hours. The reaction mixture was treated in the same manner as described in Example 30(b) and the resulting crystals were recrystallized from methanol to give 7.4 g. of 2-{3- [N'-(2-methoxyphenyl)piperazinoJpropoxy} 4 chlorochalcone dihydrochloride (Compound No. 31) having a melting point 2l5-2l8 C.

Elementary analysis for C H N O Cl-2HCl AiH O -Calculated: C, 61.11%; H, 5.95%; N, 4.92%; Cl, 18.66%. Found: C, 61.25%; H, 5.73%; N, 5.00%; Cl, 18.79%.

EXAMPLE 32 (a) To a solution of 5 g. of 2-'(3-chloropropoxy)-benzaldehyde and 3.35 g. of 4-methylacetophenone in 30 ml. of ethanol was added dropwise with agitation a solution of 1.25 g. of sodium hydroxide in 3 ml. of water under ice-cooling. After the mixture was further agitated for 3 hours under ice-cooling, a large volume of water was added to the mixture. The mixture was extracted with benzene. The benzene layer was separated, washed with water, dried over anhydrous sodium sulfate and distilled to remove benzene to give 8 g. of oily 2-(3-chloropropoxy)-4'-methylchalcone.

(b) 5.0 g. of 2-(3-chloropropoxy)-4'-methylchalcone obtained above and 4.75 g. of N-methylpiperazine were dissolved into 30 ml. of toluene. The mixture was refluxed for 8 hours and then water was added to the reaction mixture. The toluene layer was separated and extracted with diluted hydrochloric acid. The extract was made alkaline with sodium hydroxide and the resulting milky precipitate was extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium hydroxide and distilled to remove benzene. To thus obtained oily residue was added alcoholish hydrochloric acid. The resulting crystals were recrystallized. from ethanol to give 4 g. of 2-[3-N-methylpiperazino) propoxy]-4'-methylchalcone dihydrochloride (Compound No. 32) having a melting point of 210215 C.

Elementary analysis for C H N O -2HCl-%H O.- Calculated: C, 62.20%; H, 7.25%; N, 6.05%; Cl, 15.30%. Found: C, 62.43%; H, 7.38%; N, 6.05%; Cl, 15.56%.

EXAMPLE 33 To a solution of 40.2 g. of 2-(3-chloropropoxy)-4'- chlorochalcone in ml. of toluene was added 26.5 g. of N-methylpiperazine. The mixture was refluxed on oil-bath for 4 hours and filtered off to remove the precipitate. The toluene solution was washed with water and distilled to remove toluene. The resulting residue was dissolved in 500 ml. of ethanol and to the solution was added hydrogen chloride gas under cooling. The mixture was allowed to stand overnight. The resulting precipitate was separated by filtration and recrystallized from 800 ml. of ethanol to give 370 g. of 2-[3-(N'-methylpiper azino)propoxy] 4 chlorochalcone dihydrochloride (Compound No. 6) having a melting point of 225- 227 C.

Elementary analysis for C H N O Cl-2HCl'%H O. Calculated: C, 57.81%; H, 6.26%; N, 5.86%; CI, 22.26%. Found: C, 58.00%; H, 6.32%; N, 5.81%; Cl, 21.96%.

In the above method (b), by usingisobutylamine and piperazine instead of N-methylpiperazine there were pre: pared the following compounds, respectively.

2-(3-isobutylaminopropoxy)-4'-chlorochalcone oxalate (Compound No. 33) having a melting point of 172- 175 C.

2-(3-piperazinopropoxy) 4'-chlorochalcone dihydrochloride (Compound No. 34) having a melting point of 173176 C. (dec.).

EXAMPLE 34 (a) To a solution of 2 g. of 2-(3-tosyloxypropoxy)- benzaldehyde and 0.93 g. of 4-chloroacetophenone dissolved into a mixture of 10- ml. of ethanol and 20 ml. of dioxane was added dropwise with agitation a solution of 0.3 g. of sodium hydroxide in 1 ml. of water under ice-cooling. The mixture was further agitated for 3 hours under ice-cooling and allowed to stand overnight in a refrigerator. To the reaction mixture was added a large volume of water. The mixture was made acidic with hydrochloric acid and extracted with benzene. The benzene layer was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove benzene. The resulting oily residue was washed with ether, filtered and recrystallized from benzene-nhexane to give 1.1 g. of 2-(3-tosyloxypropoxy)-4'-chlorochalcone having a melting point of 114-117 C.

(b) 842 mg. of 2-(3-tosy1oxypropoxy)-4'-chlorochal cone obtained above and 800 mg. of N-methylpiperazine OCH 2-0 (CHah-N OCH; H

Same as above- 2-0 (CH2) r-N 2 Found.

C=Calculated.

18 EXAMPLE 64 To a solution of 0.46 g. of sodium in 30 ml. of ethanol was added 3.4 g. of 3-(3',4',5-trimethoxybenzoyl)coumarin. The mixture was heated to dissolve and then distilled to remove ethanol. To the resulting residue was added toluene and then the remaining ethanol was separated as the toluene azeotrope. To the toluene solution was added 1.8 g. of 3-dimethylaminopropyl chloride. The mixture was refluxed for 7 hours. After cooling, the reaction mixture was filtered and the filtrate was extracted several times with dilute hydrochloric acid. The dilute hydrochloric acid layer was saturated with sodium chloride and then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and distilled to remove chloroform. The resulting residue was recrystallized from isopropanol to give 1.55 g. of 2-(3- dimethylaminopropoxy) 3,4,5 trimethoxychalcone hydrochloride (Compound No. 8) having a melting point of 170-173 C.

The starting 3 (3,4',5-trimethoxybenzoyl)coumarin was prepared as follows:

To a solution of 17.8 g. of ethyl 3,4,5-trimethoxybenzoyl-acetate and 7.7 g. of salicylaldehyde in ml. of ethanol was added 10 drops of piperidine. The mixture was refluxed for 20 minutes (after about 5 minutes crystals appeared) and then cooled. The precipitated crystals were separated by filtration and recrystallized from chloreform-ethanol to give 14.0 g. of the desired compound having a melting point of 195-197 C.

Elementary analysis for C H O .Calculated: C, 67.05%; H, 4.74%. Found: C, 66.98%; H, 5.01%.

EXAMPLE 65 To a solution of 0.46 g. of sodium in 30 ml. of ethanol was added 3.4 g. of 3-(3,4',5-trimethoxybenzoyl)coumarin. The mixture was heated till the coumarin was dissolved into the solution and then distilled to remove ethanol. To the residue was added toluene. The mixture was treated in the same manner as described in Example 64. To the obtained toluene layer was added 2 g. of 2- dimethylaminoethyl chloride and the mixture was treated in the same manner as described in Example 64 to give 1.1 g. of 2-(Z-dimethylaminoethoxy)-3',4',5'-trimethoxychalcone hydrochloride (Compound No. 9) having a meltpoint of 168 C.

EXAMPLE 66 To a solution of 0.4 g. of sodium in 50 ml. of ethanol was added 2.8 g. of 3-(4'chlorobenzoyl)coumarin. The mixture was refluxed for 1 hour and then distilled under reduced pressure to remove ethanol. To the residue was added 30 m1. of toluene and then 3 g. of 3-diethylaminopropyl chloride was added to the toluene solution. The mixture was refluxed for 8 hours. After cooling, the toluene layer was washed with water and extracted with dilute hydrochloric acid. The dilute hydrochloric acid layer was washed with ether and extracted with chloroform. The chloroform layer was separated and distilled to remove chloroform. The resulting residue was recrystallized from ethanol to give 1.2 g. of 2-(3-diethylaminopropoxy) 4 chlorochalcone hydrochloride (Compound No. 19) having a melting point of 164-165 C.

Elementary analysis for C H NO Cl-HCl.Calculated: C, 64.82%; H, 6.68%; N, 3.44%; Cl, 17.22%. Found: C, 64.45%; H, 6.71%; N, 3.24%; Cl, 1 7.21%.

The starting 3-(4'-chlorobenzoyl)coumarin was prepared as follows:

To a solution of 41 g. of ethyl 4-chlorobenzoylacetate and 21 g. of salicylaldehyde in 210 ml. of ethanol was added 20 drops of piperidine. The mixture was refluxed for 20 minutes. After cooling, the precipitated crystals were separated by filtration and recrystallized from dimethylformaldehyde-Water to give 34.2 g. of the desired compound having a melting point of 206 C.

67.50%;'H,'3.19%; Cl, 12.45%. Found: C, 67.34%

EXAMPLE 67 To a solution of 0.4 g. of sodium in 50 ml. of ethanol EXAMPLES 68-95 In the same manner as described in Examples 66 and 67,; there were prepared various kinds of chalcone derivatives of the following formula:

R: was added 2.8 g. of 3-(4-chlorobenzoyl)coumarin. The A mixture was treated in the same manner as described in CH=CH -GO 7 {salt Example '66. To the obtained toluene solution was added 2 2.5 g. of Z-dimethylaminoethyl chloride and the mixture R was treated in the same manner as described in Example 7) 66 to give 1.3 g. of Z-(Z-dimethylaminoethoxy)-4'-chlor0- chalcone hydrochloride (Compound No. l2) having a melting point of 152-154 C. These chalcone derivatives are listed in Table III.

TABLE 111 Groups Melting Elementary analysis Ex. point Comp. No. R" i R; R; R4 11 Salt C.) C H N Cl Br No.

08.... H 00H; 11 3 HUI-H 98-100 0* 07.08 7.37 3.23 8.30

09.--- H 00H; H 3 2H01 223-225 0 00.48 0.70 5.04 14.28 4

N N-CHzUHzOH F 00.34 7.01 5.51 14.34

---- H 00H; H 3 2H01-1/ 210-211 C 00.50 0.98 5.88 14.88 5

-N N-CH; 21140 F 00.55 7.57 5.78 15.

71 -.Sameasabove H 00m H 2 2H0l-3/ -118 0 57.50 0.92 5.78 14.70 10 ZHgO F 57.34 0.98 0.17 14.83

72.... OH, H 00H, H 2 H01 178-180 0 00.38 0.08 3.87 9.80 14 13....- CI I H OCH: H 2 HO] 183-185 C 67.77 7.24 3. 59 16 74.... Same 3S8130176..;-;: H OCH: H 3 HCl 154-155 C 68.37 7.49 3.47 8.78 17 70 H 00H; H 3 H01 101-102 0 00.10 0.75 3.35 27 77..-. sameasabovenne: OCH; H 2 1101 182-188 0 65.43 0.49 3.47 8.78 28 78...: OH; H 01 3 H01 155-157 C 03.10 0.10 3.08 18.65 13 N F 03.01 0.17 3.45 18.71

79.... CzH H 01 H 2 HCl -146 C 64.08 6.40 3. 56 17.83 18 N F 03.99 0.50 3.39 18.01

CIHE

80...": H 01 H 2 HC! 182-183 C 64.96 6.20 3.4.4 17.47 23 N-0H 00H. F 02.44 5.99 4.75 18.40

82": H Cl H 3 ZHCl 225-227 C 58.80 6.22 5.96 22.64 6

--N /NCH1 F 58.87 6.431106 22.29

83": H 01 H 3 H01 208-200 0 05.71 0.47 3.33 10.87 25 H 00H; H 2 H01 192-195 0 70.00 0.51 5.84 7.40 2

85.... OCH: OCH: OCH: 3 HCl-l/ 183-184 C 64.39 7.27 2.89 7.31 26 6": H OOH: H 3 HC] 1155-168 C 88.10 8.70 3.35 8.48 27 See footnotes at end of table.

' TABLE III-Continued Groups RI N Melting Elementary analysis Ex. point Comp. No. R" R; R; R n Salt C.) C H N Cl Br No.

87-.-- H C1 H 2 2HC1 216-223 C 57.72 5.94 6.12 23. 23

NEQH, F 57.48 6.01 6.43 23.12

88-.-- OH; H Br H 2 H01 172-177 C 55.56 5.15 3.41 8.63 19.48 55 N F 55.72 5.24 3.28 8.73 19.66

89--.- Sameasabve... H Br H 3 1101 138-140 C 56.55 5.46 3.30 8.35 18.81 56 90---- CHzCH=CH H 01 H 3 H01 153-155 C 66.67 6.29 3.24 16.40 57 N F 66.72 6.06 3.27 16.66

' CHzCH=CHa 91-.-- H B1 H 2 21101 220-223 C 52.61 5.42 5.58 14.12 15.90 58 -.N, N-CH; F 52.38 5.55 5.51 14.26 16.19

92--.. H Br H 2 H01 220-223 C 58.62 5.59 3.11 7.86 17.73 59 93..-- 02H; H OH: H 2 H01 100 O 70.67 7.55 3.75 9.48 54 N/ F 70.81 7.43 3.76 9.52

94.... Sameasabove.-.-.-.;..-:.:.:.:.:-:.i.:::;:. H H H 2 HCI 146-147 C 70.02 7.00 3.89 9.35 60 95.--- OCH: OCH: OCH: 2 HO] 186-187 C 65.00 6.98 3.03 7.67 24 'C=Ca1culated; F= Found.

* "EXAMPLE 96 40 EXAMPLE 98 To a 'solution of 1.5 g. of 2-hydroxy-3,4'-dichlorochalcone in ml. of toluene was added 0.3 g. of sodium hydride (50% by weight). The mixture was refluxed for 1 hour. To the solution was added a solution of 1.4 g. of 2-diethylaminoethyl chloride in ml. of toluene. The mixture was refluxed for 4 hours, allowed to stand overnight and filtered. The filtrate was washed with water and extracted with dilute hydrochloric acid. The dilute hydrochloric acid layer was concentrated under reduced pres sure. The precipitated crystals were recrystallized from ethanol to give 1.2 g. of 2 (2 diethylaminoethoxy)- 3',4'-dichlorochalcone hydrochloride (Compound No. 61) having a melting point of 164 C.

Elementary analysis for C H NO ClfHCl.-Ca1culated: C, 58.82%; H, 5.64%; N, 3.27%; CI, 24.80%. Found: C, 58.77%; H, 5.67%; N, 3.18%; CI, 24.72%.

EXAMPLE 97 {To a' solut-ion 082.4 g. of 2 hydroxy 4' methylchalcone in ml. of toluene was added 0.6 g. of sodium hydride (50%*by weight).The mixture was heatedfor 1 hour. To the solution was added a solution of 3 g. of Z-didthylaminoethyl chloride in 30 ml. of toluene. The mixture was refluxed for 4 hours. After cooling, the precipitate was filtered 011. The resulting toluene solution was washed with water and extracted with dilute hydrochloric acid. The dilute hydrochloric acid layer was washed with ether and extracted with chloroform. The chloroform layer was distilled. The resulting residue was recrystallized from isopropanol to give 2 g. of 2-(2-diethylaminoethoxy)- 4-methylchalcone "hydrochloride (Compound No. 54) having a melting point of 100 C.

Elementary analysis for C H NO -HCl.Calculated: C, 70.67%; H, 7.55%; N, 3.75%;Cl, 9.48%. Found: C, 70.80% H, 7.49%; N, 3.76%; CI, 9.51%.

1.9 g. of 2 (2 dimethylaminoethoxy)benzaldehyde, 1.4 g. of Z-hydroxyacetophenone and 1 g. of potassium hydroxide were dissolved in 30 ml. of methanol. The mixture was refluxed for 4 hours and distilled to remove methanol. To the resulting residue was added water. The

mixture was extracted with toluene. The toluene layer was EXAMPLES 99-123 In the same manner as described in Examples 96-98, there were prepared various kinds of chalcone derivatives having the following formula:

Thus obtained various chalcone derivatives are listed in Table IV. 1

- EXAMPLE 124 2 The hypotensive activity of the present chalcone derfivatives was tested in rats, weighing 270-300 g. The test compounds were administered orally; to rats that were experimentally induced nephro genous hypertension (the blood pressure: 170-200 mm. Hg). Then, the depressor response, peak time and duration were measured (Iapanelse Circulation Journal, vol. 27,, p. 282, 1963). The results are shown in Table V.

TABLE v Depressor Peak Test compound Dose, response time Duration numb, 1 :tngJkg. (percent) (hour) (hour) 1o so -28.13 5 72 1 See the following:

EXAMPLE 125 Acute toxicity (LD of the present chalcone derivatives was tested in mice. The results are shown in Table VI.

TABLE VI Administration route Test compound number I R03 I.v 1

War oral. 3 Intravenous. I See the following:

Nos. 5, 6, 16, 25 and 26 the same as defined in Table V. halloi 20-2- (Zfiethyleminoethoxy)-3,4,5'-trimethoxyeha1eone o a e.

What is claimed is: 1. A chalcone derivative of the following formula wherein R R R R and R are the same or different, hydrogen atom, hydroxyl group, nitro group, an alkyl group having 1 to 3 carbon atoms, a halogen atom selected from chlorine, bromine and iodine or an alkoxy group having 1 to 3 carbon atoms; R R" are bound together with nitrogen atom to form morpholino or piperazine group which is unsubstituted or substituted with one or more groups selected from an alkyl group having 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms phenyl group substituted or unsubstituted with a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, benzyl group substituted orunsubstituted with hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or halogen atom, or formyl group; n is 2 or 3 and the group is substituted at ortho or meta position and the pharmaceutically acceptable acid addition salt.

2. The chalcone derivative according to claim 1, Wherein the group is a heterocyclic group selected from the group consisting of morpholino and piperazino group which is unsubstituted or substituted with one or more groups selected from an alkyl group having 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, phenyl group substituted or unsubstituted with a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms or a halogen atom, benzyl group substituted or unsubstituted with hydroxyl group, analkoxy group having 1 to 3 carbon atoms or halogen atom, or formyi group.

3. The chalcone derivative of claim 1 wherein said pharmaceutically acceptable acid addition salt is formed from an acid selected from the group consisting of hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, phosphoric acid, maleic acid, succinic acid, oxalic acid, citric acid, malic acid, tannic acid and gallic acid.

4. A chalcone derivative according to claim 1, wherein the group is a piperazino group which has at least one substitutent selected from the group consisting of an alkyl group having ing 1 to 3 carbon atoms, a hydroxyalkyl group having 1 to 3 carbon atoms, phenyl group, a phenyl group substituted by a member selected from hydroxyl group, an alkoxy group having 1 to 3 carbon atoms and a halogen atom, benzyl group, a benzyl group substituted by a member selected from hydroxyl group, an alkoxy group having 1 to 3 carbon atoms and a halogen atom and formyl group.

5. 2 [3 (N'methylpiperazino)propoxy] 4'-chlorochalcone.

6. 2-[3-(N-methylpiperazino)propoxy) 4' methoxy- I chalcone.

13. 4-[3-(N'-methylpiperazino)propoxy] 4-chlorochalcone.

14. 2-(2 morpholinoethoxy)3',4,5' trimethoxychal- 15. 2-(3-morpho1inopropoxy)-4'-methoxychalcone.

References Cited UNITED STATES PATENTS 30 OTHER REFERENCES Rossi et al.: Am. J. Pharm., vol. 129, pp. 324-331 (1957).

Rossi et al.: I. Am. Pharm. Assoc., vol. 47, pp. 640- 5 645 1958).

Packman et al.: Am. J. Pharm., vol. 134, pp. 35-40 (1962).

Banerjee et 211.: Chemical Abstracts, vol. 65, col. 20046 0 (1966) (abst. of J. Indian Chem. Soc., vol. 43, pp. 578- JOHN D. RANDOLPH, Primary Examiner U.S. C1. X.R. 

